Ibogamine congeners

ABSTRACT

The present invention is directed to compounds having formula (1), wherein n is from 0 to 8; R 1  is CH 2 OH, CH(OH)R 5 , CH 2 OR 5 , CO 2 R 5 , C(O)NH 2 , C(I)NHR 5 , C(O)NR 5 R 6 , C(O)NHNH 2 , C(O)NHNHR 5 , C(O)NHNR 5 R 6 , C(O)NR 5 NH 2 , C(O)NR 5 NHR 6 , C(O)NR 5 NR 6 R 7 , C(O)NHNH(C(O)R 5 ), C(O)NHNR 5 (C(O)R 6 ) C(O)NR 5 NH(C(O)R 6 ), C(O)NR 5 NR 6 (C(O)R 7 ), CN, or C(O)R 5 ; R 2  is H, unsubstituted or substituted alkyl, YH, YR 8 , YC(O)R 8 , C(O)YR 8 , C(O)NH 2 , C(O)NHR 8 , C(O)NR 8 R 9 , NH 2 , NHR 8 , NR 8 R 9 , NHC(O)R 8 , or NR 8 C(O)R 9 ; R 3  and R 4  are the same or different and are selected from the group consisting of H, halogens, unsubstituted or substituted alkyl, OH, OR 10 , NH 2 , NHR 10 , NR 10 R 11 , NHC(O)R 10 , or NR 10 C(O)R 11 ; R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11  are the same or different and are selected from the group consisting of unsubstituted alkyl and substituted alkyl and substituted alkyl; R 12  is selected from the group consisting of J, unsubstituted alkyl, and substituted alkyl; and Y is O or S; provided that when n is O, R 2  is selected from the group consisting of H, substituted alkyl, and unsubstituted alkyl; and pharmaceutically acceptable salts thereof. The compounds are useful in the treatment of subjects addicted to opiates and stimulants and have reduced side effects relative to other ibogamine congeners.

This application is the National Stage of International application No.PCT/US96/12627 filed Aug. 2, 1996, and claims the benefit of U.S.Provisional Patent Application Ser. No. 60/002,048, filed Aug. 8, 1995.

This invention was made with the support of the National CancerInstitute (Grant No. CA 12010) and the National Institute for Drug Abuse(Grant No. DA 03817). The Federal Government may retain certain rightsin the invention.

FIELD OF THE INVENTION

The present invention relates to ibogamine congeners and to methods fortreating addictive behavior.

BACKGROUND OF THE INVENTION

Throughout this application various publications are referenced, many inparenthesis. Full citations for these publications are provided at theend of the Detailed Description. The disclosures of these publicationsin their entireties are hereby incorporated by reference in thisapplication.

Ibogaine is one of several alkaloids found in the root bark of theAfrican shrub Tabernanthe iboga. It has a ring skeleton common withibogamine and has been identified as a potential interrupter ofaddictive behavior.

Male members of the Mitsogho people in Gabon ingest scrapings of theiboga root as part of the initiation rite into the Bwiti, a secretsociety of men. The rite of passage, which continues for several days,begins with a period of violent vomiting, followed by periods ofdrowsiness, motor incoordination, agitation, tremor, progression througha dream state, and, finally, sleep. The rite is thought to constitute anencounter with higher spiritual entities.

People who have taken purified ibogaine as an experimental drug report asimilar sequence of events lasting three days, including visions,periods of high energy accompanied by flashes of light, and, eventually,sleep. Upon waking, many drug addicts reportedly lose their craving foraddictive drugs over extended periods of time.

U.S. Pat. Nos. 4,499,096, 4,587,243, and 5,152,994, all to Lotsof,report that ibogaine is effective in treating opiate (heroin), stimulant(cocaine and amphetamine), nicotine, caffeine, and alcohol addictions.The treatment supposedly interrupts the physiological and psychologicalaspects of addiction and eliminates the desire to use drugs. In bothopiate and stimulant syndromes, a single oral treatment with ibogaine orits salts, in dosages of 6 to 19 mg/kg, is said to be effective forabout 6 months, and a series of four treatments is said to eliminateaddictive behavior for approximately 3 years. Using an animal model ofdrug addiction, several studies have sought to determine whether theseclaims can be substantiated under controlled conditions. In onepreliminary study [1], ibogaine dose-dependently decreased morphineself-administration in the hour after ibogaine treatment (acute effect)and to a lesser but significant extent, a day later (aftereffect). Insome rats there was a persistent decrease in morphine intake for severaldays or weeks after a single injection of ibogaine, whereas other ratsbegan to show such persistent changes after two to three weeklyinjections, and a few rats appeared to be entirely resistant toprolonged aftereffects. Similar effects of ibogaine on cocaineself-administration in rats were recently reported by Cappendijk andDzoljic [2].

In humans, as in rats, ibogaine's efficacy as an anti-addictive therapyappears to vary substantially from one individual to another even themost ardent supporters of ibogaine's usefulness would probably concedethat at least 30% of treated addicts do not decrease their drug intake.

Ibogaine also exhibits several side effects that limit its therapeuticutility. For example, the compound exhibits undesirable stimulant andhallucinogenic properties. In addition, ibogaine induces tremors. Verysimilar tremors are induced by harmaline, another natural alkaloid thatis chemically related to ibogaine but derived from a different plant(Peganum harmala). Both ibogaine- and harmaline-induced tremors appearto be due to activation of an olivo-cerebellar pathway [3-5], and, inrats, high doses of both agents have recently been shown to damage thecerebellar vermis, presumably as a result of overstimulation ofcerebellar Purkinje cells [5,6]. In addition ibogaine has an acuteeffect on motivated behavior during the first hour immediately followingadministration, as indicated by severely reduced bar pressing for water.

In view of the serious health effects and negative societal effectsassociated with addictive behavior, and the side effects of ibogainetreatment, the need continues for compounds which reduce addiction toaddictive substances. The present invention is directed to overcomingthis deficiency in the art.

SUMMARY OF THE INVENTION

The present invention relates to a compound having the formula:

wherein

n is from 0 to 8;

R¹ is CH₂OH, CH(OH)R⁵, CH₂OR⁵, CO₂R⁵, C(O)NH₂, C(O)NHR⁵, C(O)NR⁵R⁶,C(O)NHNH₂, C(O)NHNHR⁵, C(O)NHNR⁵R⁶, C(O)NR⁵NH₂, C(O)NR⁵NHR⁶,C(O)NR⁵NR⁶R⁷, C(O)NHNH(C(O)R⁵). C(O)NHNR⁵(C(O)R⁶), C(O)NR⁵NH(C(O)R⁶),C(O)NR⁵NR⁶(C(O)R⁷), CN, or C(O)R⁵;

R² is H, unsubstituted or substituted alkyl, YH, YR⁸, YC(O)R⁸, C(O)YR⁸,C(O)NH₂, C(O)NHR⁸, C(O)NR⁸R⁹, NH₂, NHR⁸, NR⁸R⁹, NHC(O)R⁸, or NR⁸C(O)R⁹;

R³ and R⁴ are the same or different and are selected from the groupconsisting of H, halogens, unsubstituted or substituted alkyl, OH, OR¹⁰,NH₂, NHR¹⁰, NR¹⁰R¹¹, NHC(O)R¹⁰, or NR¹⁰C(O)R¹¹;

R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are the same or different and areselected from the group consisting of unsubstituted alkyl andsubstituted alkyl;

R¹² is selected from the group consisting of H, unsubstituted alkyl, andsubstituted alkyl; and

Y is O or S;

provided that when n is 0, R² is selected from the group consisting ofH, substituted alkyl other than CH(OH)CH₃, and unsubstituted alkyl;

further provided that when n is 2, R² is OH, R¹² is H, and both R³ andR⁴ are H, R¹ is not CO₂CH₃; and

further provided that when n is 2, R² is H, R¹² is H, and R³ and R⁴ arethe same or different and are selected from the group consisting of Hand OCH₃, R¹ is not CO₂CH₃;

or pharmaceutically acceptable salts thereof.

The present invention also provides a method of treating a subjectaddicted to an addictive substance. The method includes administering tothe addicted subject an effective amount of a compound having the aboveformula, a compound having the above formula where n is 0 and R² isCH(OH)CH₃, a compound having the above formula where n is 2, R² is OH,R¹² is H, R³ and R⁴ are each H, and R¹ is CO₂CH₃, or a compound havingthe above formula where n is 2. R²is OH, R¹² is H, R³ and R⁴ are thesame or different and are selected from the group consisting of H andOCH₃, and R¹ is CO₂CH₃.

The compounds of the present invention reduce both morphine and cocaineself administration in the addicted subject but do not affect othermotivated behavior, such as bar pressing to obtain water. In addition,these compounds produce very little if any tremor, and no noticeablePurkinje cell degeneration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plot of the acute effects of 18-methoxycoronaridine onmorphine and cocaine self administration. Each data point is the mean(±S.E.) from 3-8 rats. Baseline was calculated as the average for thethree sessions preceding drug or saline (0 mg/kg) administration. Alldoses had significant effects (ANOVA and t-tests, P<0.05−0.001).

FIG. 2 is a plot of the acute effects of ibogaine, harmaline,tabernanthine, desethylcoronaridine, R-coronaridine, S-coronaridine,R-ibogamine, and S-ibogamine on morphine and cocaine selfadministration. Each data point is the mean (±S.E.) from 3-8 rats.Baseline was calculated as the average for the three sessions precedingdrug or saline (0 mg/kg) administration. All doses of all drugs hadsignificant effects (ANOVA and t-tests, P<0.05−0.001).

FIG. 3 is a bar graph showing the aftereffects of alkaloids (20 mg/kgfor desethylcoronaridine and 40 mg/kg for all others) on morphine selfadministration. Each data point is the mean (±S.E.) from 5-8 rats.‘Base’ refers to the baseline rate of responding, calculated as theaverage for the three sessions preceding drug or saline treatment. Therewere significant effects on Day 1 for all drugs and on day two for18-methoxycoronaridine, ibogaine, tabernanthine, desethylcoronaridine,R-coronaridine, and R-ibogamine (ANOVA and t-tests. P<0.05−0.001).

FIG. 4 is a bar graph showing the aftereffects of alkaloids (20 mg/kgfor desethylcoronaridine and 40 mg/kg for all others) on cocaine selfadministration. Each data point is the means (±S.E.) from 4-8 rats.‘Base’ refers to the baseline rate of responding, calculated as theaverage for the three sessions preceding drug or saline treatment. Therewere significant effects on Day 1 for all drugs and on day two for18-methoxycoronaridine, ibogaine, tabernanthine, desethylcoronaridine,R-coronaridine, and R-ibogamine (ANOVA and t-tests, P<0.05−0.001).

FIG. 5 is a bar graph showing the aftereffects of ibogaine (40 mg/kg) onbar pressing for water; presession administration on Day 1. Each datapoint is the mean (±S.E.) from six rats. ‘Base’ refers to the baselinerate of responding, calculated as the average for the three sessionspreceding ibogaine treatment. There was a significant effect on Day 1(P<0.001, t-test) but not thereafter.

FIG. 6 is a line graph showing the acute effects of18-methoxycoronaridine on bar pressing for water administeredintraperitoneally (“IP”) 15 minutes before a one hour test session. Noacute affects are noted.

DETAILED DESCRIPTION

The present invention relates to ibogamine congeners and to methods fortreating addictive behavior using these congeners. One aspect of thepresent invention relates to a compound having the formula:

R¹ is selected from the group consisting of an alcohol, an ether, anester, an amide, a hydrazide, a cyanide, or a ketone. Suitable alcoholsinclude CH₂OH and CH(OH)R⁵, suitable ethers include those having theformulae CH₂OR⁵, and suitable esters include those having the formulaeCO₂R⁵. Amides can be unsubstituted, such as C(O)NH₂, monosubstituted,such as, C(O)NHR⁵, or disubstituted, such as C(O)NR⁵R⁶. Suitablehydrazides include unsubstituted hydrazides, having the formulaC(O)NHNH₂, monosubstituted hydrazides, having the formulae C(O)NHNHR⁵ orC(O)NR⁵NH₂, disubstituted hydrazides, having the formulae C(O)NHNR⁵R⁶ orC(O)NH⁵NHR⁶, or trisubstituted hydrazides, having the formulaeC(O)NR⁵NR⁶R⁷. The hydrazides can also contain an amide functionality atthe terminal nitrogen, such as hydrazides having the formulaeC(O)NHNH(C(O)R⁵), C(O)NHNR⁵(C(O)R⁶), C(O)NR⁵NH(C(O)R⁶), orC(O)NR⁵NR⁶(C(O)R⁷). Suitable ketones are those where R¹ is C(O)R⁵.

R⁵, R⁶, and R⁷ can be either unsubstituted alkyl, such as, methyl,ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl,sec-pentyl, and neo-pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl,dodecyl, and the like, or substituted with any of a number of knownsubstituents, such as sulfo, carboxy, cyano, halogen (e.g., fluoro,chloro), hydroxy, alkenyl (e.g., allyl, 2-carboxy-allyl), alkoxy (e.g.,methoxy, ethoxy), aryl (e.g, phenyl, p-sulfophenyl), aryloxy (e.g.,phenyloxy), carboxylate (e.g., methoxycarbonyl, ethoxycarbonyl), acyloxy(e.g., acetyloxy), acyl (e.g., acetyl, propionyl), and others known tothose skilled in the art. In addition, substituted alkyls includearylalkyls, such as 2-phenyleth-1-yl, 2-phenylprop-1-yl, benzyl, andarylalkyls bearing substitutents on the aromatic ring, such as2-(5-chlorophenyl)prop-1-yl, N-piperidino, N-pyrrolidino, andN-morpholino. Each of R⁵, R⁶, and R⁷ can be the same or different andthe combination is selected primarily with consideration given to thesubstitution's effect on water-solubility and biological compatibility,although other factors, such as availability of starting materials andsynthetic ease, may enter into the selection.

Suitable esters include ethyl ester, benzyl ester, dialkylaminoalkylesters, and, preferably, methyl easter. Amides can be, for example,N-methylamide, N-ethylamide, N,N-dimethylamide, N,N-diethylamide,N-methyl-N-ethylamide, and peptides derived from amino acids and theiresters or amides. R² can also be a hydrazide, such as N′,N′-dimethylhydrazide, N′,N″-dimethylhydrazide, or preferably,unsubstituted hydrazide.

The ibogamine skeleton can be unsubstituted at the C20 position (such asin the case of desethylcoronaridine), or it can be substituted at theC20 position with an alkyl or, preferably, a derivatized alkyl. Thealkyl chain, represented in the above formula by (CH₂)_(n), can havefrom zero to eight carbons, inclusive, such as methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, and octyl, and is preferably ethyl. Thealkyl chain is derivatized with R² at the terminal carbon of the alkylchain (or, in the case where n is zero, at the C20 carbon). R² isselected from the group consisting of a hydrogen, a substituted orunsubstituted alkyl, a hydroxy, an ether, a thiol, a thioether, anamine, or an acid or thioacid derivative. In cases where n is zero, R²is preferably H or substituted or unsubstituted alkyl. Illustrativeexamples of suitable substituted or unsubstituted alkyls include thosegiven for R⁵, R⁶, and R⁷, above, Suitable ethers and thioethers have theformulae OR⁸ and SR⁸, respectively. Suitable amines includeunsubstituted amines (NH₂), monosubstituted amines (NHR⁸), ordisubstituted amines (NR⁸R⁹). Acid or thioacid derivatives can have theformulae OC(O)R⁸, SC(O)R⁸, C(O)NH₂, C(O)SR⁸, C(O)SR⁸, C(O)NHR⁸,C(O)NR⁸R⁹, NHC(O)R⁸, or NR⁸C(O)R⁹. In each of the above, R⁸ and R⁹ canbe the same or different and are selected from the group consisting ofsubstituted or unsubstituted alkyl, examples of which are the same asthose given for R⁵, R⁶, and R⁷, above. As an illustration, suitableethers and thioethers include methoxy, ethoxy, propoxy, butoxy, pentoxy,methoxyethoxymethyl ether (OCH₂OCH₂CH₂OCH₃), methylthio, ethylthio,dimethylaminoalkoxy, and sugar acetals, such as a glucoside. Suitableamine derivatives include methylamino, ethylamino, propylamino,butylamino, pentylamino, dimethylamino, diethylamino, dipropylamino,dibutylamino, methylethylamino, methylpropylamino, methylbutylamino,ethylpropylamino, ethylbutylamino, propylbutylamino, pyrrolidino,piperidino, and morpholino. Acid or thioacid derivatives can be, forexample, OC(O)CH₃, OC(O)CH₂CH₃, OC(O)(CH₂)₂CH₃, OC(O)(CH₂)₃,OC(O)(CH₂)₄CH₃, OC(O)(CH₂)₅CH₃, OC(O)(CH₂)₆CH₃, OC(O)(CH₂)₁₀CH₃,OC(O)(CH₂)₁₂CH₃, SC(O)(CH₂)₂₀CH₃, SC(O)CH₃, SC(O)CH₂CH₃, SC(O)(CH₂)₂CH₃,SC(O)(CH₂)₃CH₃, SC(O)(CH₂)₄CH₃, SC(O)(CH₂)₅CH₃, SC(O)(CH₂)₆CH₃,SC(O)(CH₂)₁₀CH₃, SC(O)(CH₂)₁₂CH₃, SC(O)(CH₂)₂₀CH₃, NHC(O)CH₃,NHC(O)CH₂CH₃, NHC(O)(CH₂)₂CH₃, NHC(O)(CH₂)₃, NHC(O)(CH₂)₁₀CH₃,NHC(O)(CH₂)₁₂CH₃, NHC(O)(CH₂)₂₀CH₃, N(CH₃)C(O)CH₃, N(CH₃)C(O)CH₂CH₃,N(CH₃)C(O)(CH₂)₂CH₃, N(CH₃)C(O)(CH₂)₃, N(CH₃)C(O)(CH₂)₁₀CH₃,N(CH₃)C(O)(CH₂)₁₂CH₃, N(CH₃)C(O)(CH₂)₂₀CH₃, and esters and amidesderived from amino acids and amino acid amides.

R³ and R⁴ can be the same or they can be different. Each can be selectedfrom hydrogen, halide (such as fluoride, chloride, bromide, and iodide),alkyl, hydroxy, ether, or amine. The alkyl can be substituted orunsubstituted and is exemplified by the substituted or unsubstitutedalkyls used to illustrate R⁵, R⁶, and R⁷. Suitable ethers have theformulae OR¹⁰ and suitable amines include unsubstituted amines (NH₂),monosubstituted amines (NHR¹⁰), or disubstituted amines (NR¹⁰R¹¹). Ineach of the above. R⁸ and R⁹ can be the same or different and areselected from the group consisting of substituted or unsubstitutedalkyl, examples of which are the same as those given for R⁵, R⁶, and R⁷,above. As an illustration R³, R⁴, or both R³ and R⁴ can be methoxy,ethoxy, propoxy, butoxy, pentoxy, methoxyethoxymethyl ether(OCH₂OCH₂CH₂OCH₃), methylamino, ethylamino, propylamino, butylamino,pentylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino,methylethylamino, methylpropylamino, methylbutylamino, ethylpropylamino,ethylbutylamino, propylbutylamino, and arylalkyl, such as benzyl. Inaddition, the R³ and R⁴ substituents can be linked via an alkylene, suchas methylene or ethylene to form a five- or six-membered ring, such aswhere R³ and R⁴, together, are —OCH₂O—, —OCH₂CH₂O—, —NHCH₂O—,—NHCH₂CH₂O—, —NHCH₂NH—, and —NHCH₂CH₂NH—,

R¹² can be a hydrogen, a substituted alkyl, such as an arylalkyl, or anunsubstituted alkyl. Suitable unsubstituted and substituted alkylsinclude those used to exemplify R⁵, R⁶, and R⁷, above.

Illustrative examples of compounds of the present invention are asfollows:

18-hydroxycoronaridine;

18-hydroxyvoacangine;

18-hydroxyconopharyngine;

16-ethoxycarbonyl-18-hydroxyibogamine;

16-ethoxycarbonyl-18-hydroxyibogaine;

16-ethoxycarbonyl-18-hydroxyibogaline;

16-hydroxymethyl-18-hydroxyibogamine;

16-hydroxymethyl-18-hydroxyibogaine;

16-hydroxymethyl-18-hydroxyibogaline;

18-methoxycoronaridine;

18-methoxyvoacangine;

18-methoxyconopharyngine;

16-ethoxycarbonyl-18-methoxyibogamine;

16-ethoxycarbonyl-18-methoxyibogaine;

16-ethoxycarbonyl-18-methoxyibogaline;

16-hydroxymethyl-18-methoxyibogamine;

16-hydroxymethyl-18-methoxyibogaine;

16-hydroxymethyl-18-methoxyibogaline;

18-benzyloxycoronaridine;

18-benzyloxyvoacangine;

18-benzyloxyconopharyngine;

16-ethoxycarbonyl-18-benzyloxyibogamine;

16-ethoxycarbonyl-18-benzyloxyibogaine;

16-ethoxycarbonyl-18-benzyloxyibogaline;

18-hydroxycoronaridine laurate;

18-hydroxyvoacangine laurate;

18-hydroxyconopharyngine laurate;

16-ethoxycarbonyl-18-hydroxyibogamine laurate;

16-ethoxycarbonyl-18-hydroxyibogaine laurate;

16-ethoxycarbonyl-18-hydroxyibogaline laurate;

18-hydroxycoronaridine acetate;

18-hydroxyvoacangine acetate;

18-hydroxyconopharyngine acetate;

16-ethoxycarbonyl-18-hydroxyibogamine acetate;

16-ethoxycarbonyl-18-hydroxyibogaine acetate;

16-ethoxycarbonyl-18-hydroxyibogaline acetate;

18-hydroxycoronaridine methoxyethoxymethyl ether;

18-hydroxyvoacangine methoxyethoxymethyl ether;

18-hydroxyconopharyngine methoxyethoxymethyl ether;

16-ethoxycarbonyl-18-hydroxyibogamine methoxyethoxymethyl ether;

16-ethoxycarbonyl-18-hydroxyibogaine methoxyethoxymethyl ether;

16-ethoxycarbonyl-18-hydroxyibogaline methoxyethoxymethyl ether;

and pharmaceutically acceptable salts thereof.

Particularly preferred are compounds having the formulae:

and pharmaceutically acceptable salts thereof.

As used herein, pharmaceutically acceptable salts are non-toxic saltswhich can be employed by those skilled in the art for in vivo use.Suitable pharmaceutically acceptable salts are the salts formed withinorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid,and phosphoric acid, metal bicarbonates, such as sodium bicarbonate,monometal phosphates, such as monosodium phosphate, and dimetalphosphates, such as disodium phosphate. The salts can also be formed byreaction with organic acids, such as carboxylic acids or sulfonic acids.Suitable carboxylic acids include acetic, propionic, glycolic, lactic,pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, cyclamic,ascorbic, maleic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic,4-aminobenzoic, anthranillic, cinnamic, salicyclic, 4-aminosalicyclic,2-phenoxybenzoic, 2-acetoxybenzoic, and mandelic acid. Suitable sulfonicacids are, for example, methanesulfonic, ethanesulfonic, andβ-hydroxyethane-sulfonic acid.

As will be recognized by those skilled in the art, the compounds of thepresent invention have four chiral carbon centers in the ibogamineskeleton. As used herein a “compound” of the present invention includescompounds having the aforementioned formulae without regard to thestereochemistry at these chiral centers. Accordingly, “compound”includes compounds which are racemic as well as to those which areoptically pure with respect to the C20. In addition, the “compounds” ofthe present invention include those which are racemic and those whichare optically pure with respect to the three bridgehead chiral carbons.

The compounds of the present invention can be synthesized using themethodology described in Bornmann [7] by reacting an appropriate3-substituted-3-(1,3-dioxolan-2-yl)butanal having the formula:

wherein

n is from 0 to 8 and

R² is H, unsubstituted alkyl, substituted alkyl, YH, YR⁸, YC(O)R⁸,C(O)YR, C(O)NH₂, C(O)NHR⁸, C(O)NR⁸R⁹, NR⁸R⁹, NHC(O)R⁸, NR⁸C(O)R⁹,NHC(O)OR⁸, NR⁸C(O)OR⁹, C(O)R⁸, or CN;

R⁸ and R⁹ are the same or different and are selected from the groupconsisting of unsubstituted or substituted alkyl; and

Y is O or S;

provided that when n is 0, R² is H, unsubstituted alkyl, or substitutedalkyl

with an indoloazepine having the formula:

wherein

R¹ is CO₂R⁵, C(O)NH₂, C(O)NHR⁵, C(O)NR⁵R⁶, C(O)NHNH(C(O)R⁵),C(O)NHN(C(O)R⁵R⁶, C(O)NHNR⁵R⁶, C(O)NR⁵NH(C(O)R⁶), C(O)NR⁵NR⁶(C(O)R⁷), orC(O)NR⁵NR⁶R⁷;

R³ and R⁴ are the same or different and are selected from the groupconsisting of H, halogens, unsubstituted or substituted alkyl, OH, OR¹⁰,NH(C(O)R¹⁰), NR¹⁰(C(O)R¹¹), or NR¹⁰R¹¹;

R⁵, R⁶, R⁷, R¹⁰, and R¹¹ are the same or different and are selected fromthe group consisting of unsubstituted or substituted alkyl; and

and R¹² is selected from the group consisting of H unsubstituted alkyl,and substituted alkyl

under conditions effective to form a condensation produce having theformula:

Typically, equimolar amounts of the two reactants are dissolved in anorganic solvent and maintained at room temperature for ½ to 72 hours,preferably for 16 hours. Suitable solvents include alcohol solvents,such as methanol, ethanol, isopropanol, and n-butanol; ester-containingsolvents, such as ethyl acetate and isopropyl acetate; ether solvents,such as tetrahydrofuran, diglyme, and dioxane; chlorinate hydrocarbons,such as methylene chloride, chloroform, and carbon tetrachloride;aromatic hydrocarbons, such as benzene, toluene, and xylene;acetonitrile; pyridine; and dimethylformamide. Preferably, a solvent ischosen in which both reactants are substantially soluble. Methanol isparticularly preferred.

After reaction is complete, the condensation product is treated in asuitable solvent with an equivalent amount of an appropriate arylalkylcontaining a good leaving group, such as an arylalkyl tosylate, anarylalkyl mesylate, or an arylalkyl halide, preferably benzyl bromide,for 0.5 to 72 hours, preferably 16 hours, at 50° C. to 120° C.,preferably at the reflux temperature of the solvent. Suitable solventsinclude lower alkanes, such as pentane, hexane, or petroleum ether;aromatic hydrocarbon solvents, such as benzene, toluene, and xylene;alcohols, such as methanol, ethanol, isopropanol, and n-butanol; andether solvents, such as diethyl ether, diglyme, or tetrahydrofuran.

Treatment of the product, with an organic-soluble Lewis base, preferablytriethylamine, produces a transient enamine acrylate having the formula:

Typical solvents for the base treatment include alcohol solvents, suchas methanol, ethanol, isopropanol, and n-butanol; ketone solvents, suchas acetone, methyl ethyl ketone, and cyclopentanone; ester-containingsolvents, such as ethyl acetate and isopropyl acetate; ether solvents,such as tetrahydrofuran, diglyme, and dioxane; chlorinated hydrocarbons,such as methylene chloride, chloroform, and carbon tetrachloride;acetonitrile; pyridine; and dimethylformamide. Preferably, a solvent ischosen in which both reactants are substantially soluble. Methanol isparticularly preferred. Base treatment can be conducted at anytemperature from room temperature to the boiling point of the solvent,but is advantageously effected with slight heating preferably from 50°C. to 70° C. for from 1 to 10 hours.

The transient enamine acrylate spontaneously cyclizes to produce aversatiline derivative having the formula:

Alternatively, the versatiline derivative can be prepared in accordancewith the method described by Kuehne [8]. Briefly, the3-substituted-3-(1,3-dioxolan-2-yl)butanal is treated with anN-arylalkyl derivative having the formula:

where R¹³ is an aryllkyl, such as benzyl. Suitable solvents for thereaction include aromatic solvents, such as benzene, toluene, andxylene; ester-containing solvents, such as ethyl acetate and isopropylacetate; ether solvents, such as tetrahydrofuran, diglyme, and dioxane;chlorinated hydrocarbons, such as methylene chloride, chloroform, andcarbon tetrachloride; acetonitrile; pyridine; and dimethylformamide.Toluene is particularly preferred. The reaction is typically conductedat a temperature from 100° C. to 120° C. preferably at reflux.

Irrespective of the route used in its preparation, the versatilinederivative is then converted to a cleavamine having the formula:

by reduction with, for example, sodium borohydride in an acidic solvent,preferably acetic acid. The reduction is effected by heating, preferablyto a temperature between 80° C. and 110° C., more preferably between 85°C. and 95° C.

Reduction, preferably catalytic reduction using H₂ over palladium/carboncatalyst, followed by treatment with acidic alcohol, preferably withhydrochloric acid in methanol, followed by addition of a base, such asammonium hydroxide, yields an enamine having the formula:

The enamine is then heated, preferably at between 80° C. and 120° C. for4 to 12 hours in a suitable solvent, to produce a compound of thepresent invention having the formula 1:

Suitable solvents include aromatic solvents, such as benzene, toluene,and xylene; ether solvents, such as tetrahydrofuran, diglyme, anddioxane; chlorinated hydrocarbons, such as methylene chloride,chloroform, and carbon tetrachloride; acetonitrile; pyridine; anddimethylformamide. Toluene is particularly preferred. Alternatively, thecompound of the present invention can be prepared by storing the enamineunder vacuum or in an inert atmosphere, such as under argon or nitrogen,for at least 12 hours, preferably 4 days to 6 days.

As an alternative to using a 3-substituted-(1,3-dioxolan)-2-yl)butanal,where R² is hydroxy, compounds of the present invention bearing a C18hydroxyalkyl moiety (1(R²═OH) can also be prepared by reduction of thecorresponding C18 alkyl ester (such as, 1(R²═COOR⁵)), for example, witha half-molar equivalent of lithium aluminum hydride or withdiisobutylaluminum hydride. Compounds bearing the alkoxyalkyl moiety(1(R²═OR⁵)) can likewise be prepared from the corresponding esters(1(R²═COOR⁵)), such as by reduction with LiAlH₄/AlCl₃. In a similarmanner, it can be advantageous to prepare compounds of the presentinvention having basic amines (such as 1(R²═NH₂ or R²═NHR⁸)) from thecorresponding amides (such as 1 (R²═NHC(O)R⁸ or R²═NR⁸C(O)R⁹)) byhyrdrolysis with aqueous acid rather that by starting withamine-containing 3-substituted-(1,3-dioxolan)-2-yl)butanal. The amide toamine conversion can also be effected by conventional procedures, suchas with diisobutylaluminum hydride in an ether, preferablytetrahydrofuran (“THF”) to give a substituted amine. Again, thisalternative method is particularly advantageous when n is less thanthree.

Compounds having C16 hydroxy or alkoxymethyl substitutents are preparedby reduction of the corresponding C16 ester, such as with LiAlH₄/THF tothe C16 hydroxymethyl or with LiAlH₄/AlCl₃ to the C16 alkoxymethyl.Reduction of C16 amides with LiAlH₄ would provide C16 amines. C16hydrazides containing basic nitrogens (such as 1 (R¹═C(O)NHNH₂,C(O)NHNR⁵, C(O)NR⁵NH₂, or C(O)NR⁵NHR⁶) can be prepared from thecorresponding hydrazide carbamates, typically t-butyl carbamate, byhydrolysis with acids.

Subsequent to preparation, the compound of the present invention canoptionally be purified by recrystallization, solvent extraction using,for example, a Soxhlet extraction apparatus, chromatography, such asHPLC or conventional column chromatography, or other conventionalpurification methods. In addition, prior to, subsequent to, or as an aidin isolation, the compounds of the present invention can be converted tothe acid addition salt, such as by contacting a solution of the compoundwith an appropriate acid.

Preparation of the 3-substituted-(1,3-dioxolan-2-yl)butanal startingmaterials, is achieved by conventional methods. Typically thesereactants are prepared by oxidation of a 2-substituted-4-hydroxybutyricester. The latter can be obtained by alkylation of a allylmalonic esterwith an alkyl halide and a base (e.g. sodium alkoxide) followed bydecarboalkoxylation with LiCl, hydroboration with diborane or withborane dimethylsulfide complex, and oxidation with hydrogen peroxide andsodium hydroxide. Oxidation of the 4-hydroxy-2-substituted butanoicester is achieved with dimethyl sulfoxide and oxalyl chloride. Theresulting aldehyde is protected, preferably as its acetal with ethyleneglycol. Reduction of the ester function, such as with LiAlH₄, isfollowed by oxidation of the resultant alcohol with dimethylsulfoxideand oxalyl chloride.

The indoloazepine starting material, with which the butanal is reacted,is typically prepared by methods which have been well-developed in theart, such as those described in references [9-13]. Briefly, theindoloazepine starting material can be prepared by condensation oftryptamine with methyl 3-chloropyruvate. The resulting carboline isheated in pyridine to provide an unsaturated indoloazepine (vinylogousurethane). The latter is reduced with sodium cyanoborohydride.

When using the alternative route to the preparation of versatilinederivatives, the appropriately substituted N^(b)-benzylindoloazepine isprepared by alkylation of the above N^(b)-H indoloazepine with benzylbromide and sodium carbonate. Alternatively, indoloazepines withsubstituents on the aromatic ring can be made by Fischer Indolesynthesis from substituted phenylhydrazines and N-benzyl-4-piperidones,followed by reaction with t-butyl hypochlorite and thallium dimethylmalonate, and, then, with lithium chloride.

The compounds of the present invention are useful in treating subjects,such as mammals and including rats and humans, exhibiting addictivebehavior, by administering the compounds to such subjects in aneffective amount. The compounds of the present invention may beadministered alone or in combination with suitable pharmaceuticalcarriers or diluents. The diluent or carrier ingredients should beselected so that they do not diminish the therapeutic effects of thecompounds of the present invention.

The compounds herein may be made up in any suitable form appropriate forthe desired use; e.g., oral, parenteral, or topical administration.Examples of parenteral administration are intraventricular,intracerebral, intramuscular, intravenous, intraperitoneal, rectal, andsubcutaneous administration.

Suitable dosage forms for oral use include tablets, dispersible powders,granules, capsules, suspensions, syrups, and elixirs. Inert diluents andcarriers for tablets include, for example, calcium carbonate, sodiumcarbonate, lactose, and talc. Tablets may also contain granulating anddisintegrating agents such as starch and alginic acid, binding agentssuch as starch, gelatin, and acacia, and lubricating agents such asmagnesium stearate, stearic acid, and talc. Tablets may be uncoated ormay be coated by known techniques to delay disintegration andabsorption. Inert diluents and carriers which may be used in capsulesinclude, for example, calcium carbonate, calcium phosphate, and kaolin.Suspensions, syrups, and elixirs may contain conventional excipients,for example, methyl cellulose, tragacanth, sodium alginate; wettingagents, such as lecithin and polyoxyethylene stearate; andpreservatives, e.g., ethyl-p-hydroxybenzoate.

Dosage forms suitable for parenteral administration include solutions,suspensions, dispersions, emulsions, and the like. They may also bemanufactured in the form of sterile solid compositions which can bedissolved or suspended in sterile injectable medium immediately beforeuse. They may contain suspending or dispersing agents known in the art.

One aspect of the present invention is directed to therapeuticallytreating a subject suffering from an addiction to an addictivesubstance. In particular, the compounds of the present invention areuseful where the addictive substance is a barbituate; an opiate, such asmorphine, codeine, heroin, levorphanol, meperidine, methadone,propoxyphene, acetylmethadol (LAAM), pentazocine, butorphanol,nalbuphine, buprenorphine, dezocine, fentanyl, and combinations of theseopiates; a stimulant, such as d-amphetamine, 1-amphetamine,d1-amphetamine, methamphetamine, benzphetamine, phentermine,diethylpropion, phenmetrazine, phendimetrazine, chlorphentermine,clortermine, mazindol, phenylpropanolamine, cocaine, methylphenidate,nicotine, cathinone (khat plant), and combinations of these stimulants;a depressant, such as meprobamate, chlordiazepoxide, diazepam, oxazepam,lorazepam, flurazepam, prazepam, chlorazepate, alprazolam, triazolam,temazepam, halazepam, quadazepam, midazolam, estazolam, ethanol,pentobarbital, phenobarbital, secobarbital, amobarbital, andcombinations of these depressants; or combinations of these addictivesubstances. The subject can be addicted to one of these addictivesubstances or to a plurality of these addictive substances.

Treatment comprises administering to the mammal an effective amount of acompound having the formula:

wherein

n is from 0 to 8;

R¹ is CH₂OH, CH(OH)R⁵, CH₂OR⁵, CO₂R⁵, C(O)NH₂, C(O)NHR⁵, C(O)NR⁵R⁶,C(O)NHNH₂, C(O)NHNHR⁵, C(O)NHNR⁵R⁶, C(O)NR⁵NH₂, C(O)NR⁵NHR⁶,C(O)NR⁵NR⁶R⁷, C(O)NHNH(C(O)R⁵), C(O)NHNR⁵(C(O)R⁶), C(O)NR⁵NH(C(O)R⁶),C(O)NR⁵NR⁶(C(O)R⁷), CN, or C(O)R⁵;

R² is H, unsubstituted or substituted alkyl, YH, YR⁸, YC(O)R⁸, C(O)YR⁸,C(O)NH₂, C(O)NHR⁸, C(O)NR⁸R⁹, NH₂, NHR⁸, NR⁸R⁹, NHC(O)R⁸, or NR⁸C(O)R⁹;

R³ and R⁴ are the same or different and are selected from the groupconsisting of H, halogens, unsubstituted or substituted alkyl, OH, OR¹⁰,NH₂, NHR¹⁰, NR¹⁰R¹¹, NHC(O)R¹⁰, or NR¹⁰C(O)R¹¹;

R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are the same or different and areselected from the group consisting of unsubstituted alkyl andsubstituted alkyl;

R¹² is selected from the group consisting H, unsubstituted alkyl, andsubstituted alkyl; and

Y is O or S;

provided that when n is O, R² is selected from the group consisting ofH, substituted alkyl, and unsubstituted alkyl;

or a pharmaceutically acceptable salt thereof.

It will be appreciated that the actual preferred amount of compound ofthe present invention used will vary according to the particularcompound, the particular composition formulated, and the mode ofapplication. Many factors that modify the action will be taken intoaccount by those skilled in the art; e.g., body weight, sex, diet, timeof administration, route of administration, rate of excretion, conditionof the host, drug combinations, reaction sensitivities and severitiesand severity of addiction. Administration can be carried outcontinuously or periodically within the maximum tolerated dose. Optimalapplication rates for a given set of conditions can be ascertained bythose skilled in the art using conventional dosage administration testsin view of the above guidelines. Preferably the compound is administeredin a dose from about 1.0 to about 80 mg/kg of the subject's mass.

The present invention is further illustrated by the following examples.

EXAMPLES

Ibogamine congeners were synthesized as described in detail below withreference to the following reaction scheme:

Example 1 Diethyl 2-(2-methoxyethyl)-2-allylmalonate (2).

Metallic sodium (15 g, 230 mmol) was dissolved in dry ethanol (250 mL)with cooling in an ice bath, under nitrogen, and diethyl allylmalonate(Lancaster Synthesis, Windham, Mass.) (105 g, 525 mmol) in absoluteethanol (50 mL) was added dropwise under nitrogen. The mixture wasstirred at room temperature for 1 h. and 2-bromoethyl methyl ether(87.57 g, 630 mmol) in absolute ethanol (50 mL) was then added dropwise.The mixture was heated at reflux for 3 h and then cooled to roomtemperature. The precipitate solid was filtered and washed with ethanol(2×100 mL). The residue obtained upon concentration of the filtrate wasdiluted with water (1 L). The mixture was extracted with ether (2×150mL), dried over MgSO₄ and concentrated to give the diester ether 2 (118g, 87%) as a viscous liquid. IR (KBr) υ_(max) 3069, 2971, 2927, 1734,1640, 1459, 1443, 1382, 1361, 1284, 1223, 1196, 1119, 1077, 1031, 922,856 cm⁻¹: ¹HNMR (CDCl₃) δ1.24 t, J=7.0 Hz, 6 H), 2.17 (t, J=6.4 Hz, 2H), 2.68 (d, J=7.1 Hz, 2 H), 3.2 (s, 3 H), 3.41 (t, J=6.5 Hz, 2 H), 4.17(dis q, 4 H), 5.04-5.12 (m, 2 H), 5.63-5.79 (m, 1 H); ¹³CNMR (CDCl₃)δ13.98, 32.05, 37.31, 55.08, 58.52, 61.13, 68.34, 118.93, 132.49,170.17; mass spectrum (EI), m/z (rel itensity) 259 (M⁺+1.16), 227 (20),213 (19), 200 (37), 185 (13), 167 (17), 154 (25), 153 (65), 139 (38),125 (25), 108 (100), 81 (30), 79 (31), 67 (23), 59 (23), 53 (23).

Example 2 Ethyl 2-(2-methoxyethyl)-pent-4-enoate (3)

A mixture of diester 2 (40 g, 155 mmol), prepared according to Example1, and lithium chloride (13 g, 300 mmol) in DMSO (100 mL). DMF (20 mL),and water (2 mL) was heated to 170° C. for 6 h and cooled to roomtemperature. The mixture was poured into water (250 mL), extracted withCH₂Cl₂ (3×100 mL), and dried over MgSO₄. The solvent was removed underreduced pressure to afford the monoester ether 3 (25.2 g, 87%); IR (KBr)υ_(max) 3079, 2974, 2921, 2869, 1732, 1640, 1461, 1443, 1470, 1374,1177, 1121, 1029, 990, 916, 855 cm⁻¹; ¹HNMR (CDCl₃) δ1.25 (t, J=7.05 Hz,3H), 1.65-1.75 (m, 1H), 1.85-1.95 (m, 1H), 2.20-2.40 (m, 2H), 2.50-2.60(m, 1H), 3.30 (s, 3H), 3.35-3.45 (m, 2H), 4.13 (q, J=7.05, 2H),5.00-5.07 (dd, J=10.2, 25 Hz, 2H), 5.71-5.74 (m, 1H); ¹³CNMR (CDCl₃)δ14.21, 31.44, 36.45, 42.12, 58.48, 60.12, 70.37, 70.38, 116.79, 135.19,175.19; mass spectrum (EI), m/Z (rel intensity) 223 (11), 200 (19), 185(M-1, 4.5), 154 (19), 153 (46), 143 (33), 128 (33), 121 (37), 120 (34),112 (22), 108 (88), 95 (28), 82 (41), 81 (98), 79 (94), 59 (38), 57(71), 55 (100), 54 (38), 53 (59),

Example 3 2-(2-Methoxyethyl)-pent-4-en-1-ol (4)

A 1M solution of lithium aluminum hydride (135 mL), 134 mmol) was addedvia cannula to a stirred solution of the ester 3 (25 g, 134 mmol),prepared according to Example 2, in dry ether (200 mL). The mixture wasstirred for 2 h at room temperature under nitrogen and cooled to 0° C.,and water (10 mL) was added dropwise, with stirring, followed bydropwise addition of 15% NaOH (10 mL) and water (30 mL) at 0° C. toproduce a white precipitate. The precipitate was filtered, and washedwith ether (2×50 mL). The filtrate was dried over MgSO₄, filtered, andconcentrated to give the alcohol 4 (16.5 g, 85.4%). IR (KBr) υ_(max)34,10, 3071, 2930, 2860, 1641, 1442, 1384, 1185, 1109, 1043, 993, 911cm⁻¹; ¹HNMR (CDCl₃) δ1.61-1.75 (m, 3 H), 2.02-2.30 (m, 2 H), 3.35 (s, 3H), 3.36-3.60 (m, 4 H), 5.01-5.06 (m, 2 H), 5.77-5.79 (m, 1 H); ¹³CNMR(CDCl₃): δ31.33, 35.95, 38.56, 58.20, 65.17, 70.98, 116.07, 136.59; massspectrum (EI), m/z (rel intensity) 145 (7), 144 (M⁺, 3), 143 (23), 126(15), 113 (20), 111 (42), 102 (17), 95 (27), 94 (57), 93 (31), 83 (49),82 (41), 81 (61), 79 (100), 71 (70), 70 (42), 69 (38), 67 (65), 58 (46),57 (34), 55 (75), 54 (48), 53 (34).

Example 4 2-(2-Methoxyethyl)-4-penten-1-al (5)

Dry dimethylsulfoxide (18.4 mL, 260 mmol) in dry CH₂Cl₂ (30 mL) wasadded dropwise to a stirred solution of 2M (COCl)₂ (65 mL, 130 mmol) at−78° C. during 15 min under nitrogen. The alcohol 4 (15 g, 104 mmol),prepared according to Example 3, in dry dichloromethane (50 mL) was thenadded during 10 min. resulting in a slightly cloudy solution, which wasstirred for 30 min at −78° C. A solution of triethyl amine (75 mL, 520mmol) in dichloromethane (50 mL) was then added dropwise during 15 min.The mixture was then stirred for 1h at room temperature, and thereaction was quenched by adding water (25 mL), with rapid stirring. Theresulting slurry was immediately poured into ether (300 mL) and washedwith 20% KHSO₄ (2×200 mL). The layers were separated, and the aqueouslayer was extracted with ether (2×100 mL). The combined organic layerswere washed with brine solution (2×100 mL), dried over MgSO₄, filtered,and concentrated to afford the crude aldehyde 5 (12.4 g, 84%) as an oil,which was used in the following condensation with ethylene glycol, IR(KBr) υ_(max) 2951, 2921, 2863, 1720, 1638, 1456, 1379, 1255, 1121,1033, 997, 909 cm⁻¹; ¹HNMR (CDCl₃) δ1.73-1.77 (m, 1 H), 1.92-1.96 (m, 1H), 2.23-2.27 (m, 1 H), 2.42-2.46 (m, 1 H), 2.50-2.52 (m, 1 H), 3.29 (s,3 H), 3.39-3.43 (m, 2 H), 5.05-5.10 (m, 2 H), 5.72-5.77 (m, 1 H), 9.64(s, 1 H); ¹³CNMR (CDCl₃) δ28.65, 33.04, 48.57, 58.57, 70.00, 117.40,134.85; mass spectrum (EI), m/z (rel intensity) 167 (23), 157 (17), 149(100), 143 (16), 142 (4, M⁺), 141 (12), 129 (28), 127 (64), 112 (22),111 (26), 109 (14), 100 (16), 97 (23), 95 (31), 93 (22), 87 (24), 85(36), 84 (53), 83 (45), 82 (21), 81 (49), 79 (27), 71 (70), 70 (26), 69(51), 67 (55), 59 (49), 57 (80), 55 (87), 53 (31).

Example 5 4-(1,3-Dioxolan-2yl)-6-methoxy-1-hexane (6)

A stirred solution of crude aldehyde 5 (12.4 g, 87.20 mmol), preparedaccording to Example 4, ethylene glycol (8.1 g, 130 mmol), p-toluenesulfonic acid monohydrate (1 g) in dry benzene (200 mL) contained in a500 mL round-bottom flask fitted with a Dean Stark trap was heated atreflux for 12 hrs. The mixture was cooled to room temperature, thebenzene layer was separated, and the aqueous layer was extracted withether (2×100 ml). Combined organic layers were dried over MgSO₄ andfiltered. The residue obtained on concentration was purified by flashcolumn chromatography on silica gel using ether/hexane (1:1) as eluantto give 6 (14.5 g, 89%) as an oil. IR (KBr) υ_(max) 2981, 2934, 2832,1637, 1457, 1388, 1119, 1036, 988, 947, 906 cm⁻¹; ¹HNMR (CDCl₃)δ1.57-1.85 (m, 3H), 2.09-2.45 (m, 2H), 3.31 (s, 3H), 3.44 (t, J=6.4 Hz,2H), 3.83-3.94 (m, 4H), 4.81 (s, 1H, 4.99-5.07 (m, 2H), 5.75-5.90 (m,1H); ¹³CNMR (CDCl₃) δ28.42, 33.83, 58.29, 64.82, 64.92, 70.87, 106.01,116.07, 136.66: mass spectrum (EI), m/Z (rel intensity) 186 (M⁺, 9), 155(11), 141 (9), 127 (10), 111(11), 99 (30), 84 (32), 79 (29), 73 (100),55 (7).

Example 6 4-(1,3-Dioxolan-2-yl)-6-methoxyhexan-1-ol (7)

A 1M solution of borane-methyl sulfide complex in dichloromethane (18mL, 18 mmol) was added dropwise to a stirred solution of the olefinicacetal 6 (10 g, 53.7 mmol), prepared according to Example 5, in hexane(40 mL) at 0° C. The mixture was stirred for 3 h at room temperature andthen cooled to 0° C., and then absolute ethanol (10 mL) was addeddropwise, followed by 15% NaOH (10 mL) and 30% H₂O₂ (10 mL). Thereaction mixture was heated at reflux for 1 h, cooled to roomtemperature, and poured into water (200 mL). The organic layer wasseparated, and the aqueous layer was extracted with ether (3×50 mL). Theorganic layers were combined, dried over MgSO₄, and concentrated underreduced pressure. The crude product was chromatographed on a silica gelcolumn, eluting with 2% methanol in ether, to give the alcohol 7 (6.1 g,56%) as a viscous liquid. IR (KBr) υ_(max) 3434, 2929, 2808, 1646, 1451,1403, 1111, 953 cm⁻¹; ¹HNMR (CDCl₃) δ1.30-1.85 (m, 7 H), 3.30 (s, 3 H),3.43-3.50 (m, 2 H), 3.61 (t, J=6.3 Hz, 2 H), 3.83-4.00 (m, 4 H), 4.79(d, J=3.7 Hz, 1 H); ¹³CNMR (CDCl₃) δ25.44, 29.04, 30.15, 58.33, 62.66,64.78, 64.84, 70.98, 106.45, 33.83, 58.29, 64.82, 64.92, 70.87, 106.01:mass spectrum (EI), m/z (rel intensity) 159 (M⁺−45, 6.4), 143 (29), 127(95), 111 (35), 73 (100), 67 (7), 55 (83).

Example 7 4-(1,3-Dioxolan-2-yl)-6-methoxyhexanal (8).

The alcohol 7 (6 g, 29.37 mmol), prepared according to Example 6, wasoxidized using 2M (COCl)₂ (18 mL, 36 mmol), dry DMSO (5.1 mL, 72 mmol)and triethyl amine (20.7 mL, 144 mmol) analogous to the oxidation of thealcohol 4, as described in example 4. Similar work up as for 5 gave thealdehyde 8 (4.8 g, 81%) as a colorless oil. IR (KBr) υ_(max) 2939, 2880,2735, 1719, 1451, 1391, 1111, 1038, 947 cm⁻¹: ¹HNMR (CDCl₃) δ1.45-2.85(m, 5 H), 2.54 (t, J=6.8 Hz, 2 H), 3.31 (s, 3 H), 3.43-3.46 (m, 2 H),3.83-3.95 (m, 4 H), 2.54 (t, J=6.8 Hz, 2 H), 3.31 (s, 3 H), 3.43-3.46(m, 2 H), 3.83-3.95 (M, 4 H), 4.77 (d, J=3.3 Hz, 1 H), 9.76 (t, J=1.5Hz, 1 H); ¹³CNMR (CDCl₃) δ21.51, 29.23, 37.99, 41.72, 58.42, 64.81,64.88, 70.66, 106.26, 202.39: mass spectrum (EI), m/z (rel intensity)210 (33), 202 (M⁺, 3), 201 (15), 157 (19), 144 (27), 143 (38), 141 (19),127 (17), 126 (1), 111 (30), 109 (12), 100 (4), 99 (11), 73 (100), 59(10), 57 (8), 55 (12), 54 (5).

Example 8 2-Benzyloxy bromide (9)

To a suspension of triphenylphosphine (69 g, 263 mmol) in anhydrousacetonitrile (200 mL) was added bromine (13.6 mL, 263 mmol), dropwise,with stirring at 0° C. over 15 min, and then 2-benzyloxyethanol (40 g,263 mmol) (Aldrich Chemical Co., St. Louis, Mo.) in dry acetonitrile (25mL) was added dropwise at 0° C. over 30 min. The yellow colored solutionwas stirred for an additional 30 min at 0° C., and the solvent wasevaporated under reduced pressure. The residue was suspended in ether(200 mL), and the precipitated solid was filtered and washed with ether(3×100 mL). The filtrate was concentrated, and the residue waschromatographed on a silica gel column, eluting with ether/hexane (1:4)to give 9 (43 g, 77%) as a pale yellow liquid. IR (KBr) υ_(max) 3087,3063, 3030, 2964, 2859, 1495, 1453, 1422, 1360, 1276, 1205, 1110, 1040,1028, 738, 698, 672 cm⁻¹; ¹HNMR (CDCl₃) δ3.47 (t, J=6 Hz, 2 H), 3.77 (t,J=6 Hz, 2 H), 4.57 (s, 2 H), 7.28-7.35 (m, 5 H); ¹³CNMR (CDCl₃) δ30.39,69.99, 73.14, 127.72, 127.84, 128.47, 137.76.

Example 9 Diethyl 2-(2-Benzyloxyethyl)-allylmalonate (10)

Sodium (5.3 g, 230 mmol) was dissolved in dry ethanol with cooling in anice bath and diethyl allylmalonate (36.84 g, 184 mmol) in absoluteethanol (50 mL) was added dropwise, under nitrogen. The mixture wasstirred at room temperature for 1 h, and the bromide 9 (39.62 g, 184.2mmol), prepared according to Example 8, in absolute ethanol (50 mL) wasadded dropwise. The mixture was heated to 60° C. for 3 h and cooled toroom temperature. Precipitated solid was filtered and washed withethanol (2×50 mL). The residue obtained upon concentration of thefiltrate was diluted with water (500 mL). The mixture was extracted withether (3×100 mL), dried over MgSO₄, and concentrated to give a viscousliquid (54 g). ¹HNMR of this product showed a 3:1 ratio of 10 andbenzyloxy-2-ethoxy ethanol. The mixture of products was inseparable bychromatography and hence the mixture was directly subjected todecarboethoxylation. IR (KBr) ν_(max) 3077, 2989, 2874, 1741, 1456,1347, 1279, 1220, 1201, 1106, 1030, 926, 858, 741, 702, cm⁻¹; ¹HNMR(CDCl₃) δ 1.19 (t, J=7.4 Hz, 6 H), 2.24 (t, J=6.5 Hz 2 H), 2.69 (d,J=7.4 Hz, 2 H), 3.51 (t, J=6.5 Hz, 2 H), 4.13 (q, J=7.4 Hz, 4 H), 4.43(s, 2 H), 5.04-5.07 (m, 2 H), 5.60-5.70 (m, 1 H), 7.20-7.40 (m, 5 H);¹³CNMR (CDCl₃) δ 13.88, 32.01, 37.08, 55.57, 61.01, 65.78, 72.83,118.78, 127.31, 127.46, 128.06, 132.40, 138.10, 170.82; mass spectrum(EI), m/z (rel intensity) 335 (1.2), 334 (M⁺,0.75), 249 (9.5),2.77 (15),203 (22), 200 (60), 180 (40), 143 (17), 134 (22), 127 (22), 125 (15),109 (25), 108 (70), 107 (90), 105 (55), 91 (100), 89 (15), 65 (14).

EXAMPLE 10 Ethyl 2-(2-Benzyloxyethyl)-pent-4-enoate (11)

A mixture of crude diester 10 (54 g), prepared according to Example 9,and lithium chloride (10.1 g, 234.67 mmol) in DMSO (78 mL), DMF (15 mL),and water (1.5 mL) was heated at 170° C. for 6 h and cooled to roomtemperature. The mixture was poured into water (250 mL) and extractedwith CH₂Cl₂(3×100 mL), and the extract was dried over MgSO₄. The solventwas removed under reduced pressure to afford crude monoester 11 (44 g).IR (KBr) ν_(max) 3065, 3029, 2981, 2928, 2863, 1729, 1642, 1496, 1451,1378, 1179, 1106, 1025, 996, 915, 853, 737, 696 cm⁻¹; ¹HNMR (CDCl₃)δ1.19 (t, J=6.9 Hz, 3 H), 1.75-1.79 (m, 1 H), 1.93-1.97 (m 1 H),2.22-2.38 (m, 2 H), 2.62-2.63 (m, 1 H), 3.42-3.57 (m, 2 H), 4.04-4.12(m, 2 H), 4.45 (s 2 H), 5.01-5.02 (m, 2 H), 5.70-5.75 (m, 1 H),7.23-7.33 (m, 5 H); ¹³CNMR (CDCl₃)δ 14.00, 31.45, 36.36, 42.05, 59.97,67.83, 72.76, 116.82, 127.33, 127.36, 127.54, 128.22, 138.20, 175.04;mass spectrum (EI), m/z (rel intensity) 263 (M⁺−1.1.7), 180 (3.4), 171(2.6), 156 (12), 155 (11), 131 (3), 128 (23), 107 (14), 101(8), 100(10), 97 (4), 92 (11), 91 (100), 89 (8), 81 (7), 79 (11), 77 (7), 73(14), 69 (9), 67 (8), 65 (14).

EXAMPLE 11 2-(2Benzyloxyethyl)-pent-4-en-1-ol (12)

A 1 M solution of lithium aluminium hydride (122 mL, 122 mmol) was addedvia cannula to a stirred solution of crude ester 11 (44 g), preparedaccording to Example 10, in dry ether (150 mL). The mixture was stirredfor 2 h at room temperature under nitrogen, cooled to 0° C. and water (9mL) was added dropwise with stirring, followed by 15% NaOH (9 mL) andwater (27 mL), which was added dropwise at 0° C. to produce a whiteprecipitate. The precipitate was filtered and washed with ether (2×50mL). The filtrate was dried over MgSO₄. The residue, obtained uponconcentration, was subjected to column chromatography on silica gel.Contaminant benzyloxy-2-ethoxy ethanol (12.4 g) was first eluted withether/hexane (2:1) while the alcohol 12(24 g, 59% based on diethylallylmalonate) was eluted with 2% methanol in ether. IR (KBr) ν_(max)3404, 3071, 3033, 2930, 2868, 1640, 1498, 1454, 1361, 1202, 1100, 1042,996, 916, 838, 697 cm⁻¹; ¹HNMR (CDCl₃) δ 1.63-1.73 (m, 3 H), 2.02-2.15(m, 2 H), 2.84 (t, J=5.8 Hz, 1 H), 3.45-3.58 (m, 4 H), 4.49 (s, 2 H),5.00-5.03 (m, 2 H), 5.70-5.85 (m, 1 H), 7.26-7.35 (m, 5 H); ¹³CNMR(CDCl₃) δ 31.65, 3620, 3891, 53.36, 65.58, 68.66, 73.13, 116.28, 127.69,127.71, 128.39, 136.75, 137.88: mass spectrum (EI), m/z (rel intensity)263 (M⁺+1.10), 203 (1.5), 185 (2.3), 181 (3.5), 143 (2.5), 129 (5), 111(6), 108 (6), 107 (22), 95 (5), 93 (6), 92 (12), 91 (100), 81 (16), 79(10), 77 (5), 67 (10), 65 (13).

EXAMPLE 12 4-(1,3-Dioxolan-2-yl)-6-benzyloxyhex-1-ene (14)

Dry DMSO (19.36 mL, 273.6 mmol) in dry CH₂Cl₂ (35 mL) was added dropwiseto a stirred solution of 2 M (COCl)₂ (68.40 mL, 136.8 mmol) at −78° C.during 15 min. The alcohol 12 (24 g, 109.44 mmol), prepared according toExample 11 , in dry dichloromethane (50 mL) was then added during 10min, resulting in a slightly cloudy solution. This was stirred for 30min at −78° C. and a solution of triethyl amine (79 mL, 547.2 mmol) indichloromethane (50 mL) was then added dropwise during 15 min. Themixture was stirred for 30 min at −78° C. and 30 min at 0° C. Thereaction was quenched by adding water (25 mL) with rapid stirring. Theresulting slurry was immediately poured into ether (300 mL) and washedwith 20% KHSO₄ (2×200 mL). The layers were separated and the aqueouslayer was extracted with ether (2×100 mL). The combined organic layerswere washed with brine solution (2×100 mL), dried over MgSO₄, filtered,and concentrated to afford crude aldehyde 13 (22 g) which wasimmediately used for protection. A stirred solution of crude 13 (22 g,101.25 mmol), ethylene glycol (9.4 g, 151.87 mmol), andp-toluenesulfonic acid monohydrate (1 g) in dry benzene (200 mL),contained in a 500 mL round-bottom flask fitted with a Dean Stark trap,was heated at reflux for 12 h. The mixture was cooled to roomtemperature, the benzene layer was separated, and the aqueous layer wasextracted with ether (2×100 mL). The combined organic layers were driedover MgSO₄ and filtered. The residue obtained on concentration waspurified by column chromatography on silica gel, using ether/hexane(1:1) as eluant, to give acetal 14 (21 g, 73.5%) as an oil. IR (KBr)ν_(max) 3066, 3030, 2927, 2881, 1642, 1457, 1400, 1365, 1208, 1156,1100, 1028, 946, 739, 628 cm⁻¹; ¹HNMR (CDCl₃) δ 1.62-1.66 (m, 1 H),1.79-1.91 (m, 2 H), 2.08-2.11 (m, 1 H), 2.25-2.28 (m, 1 H), 3.54 (t,J=6.9 Hz, 2 H), 3.78-3.90 (m, 4 H), 4.47 (s, 2 H), 4.80 (d, J=3.8 Hz, 1H), 4.97-5.04 (m, 2 H), 5.77-5.82 (m, 1 H), 7.23-7.34 (m, 5 H); ¹³CNMR(CDCl₃) δ 28.55, 33.78, 38.33, 64.77, 64.86, 68.40, 72.59, 106.00,116.04, 127.29, 127.45, 128.16, 136.66, 138.62; mass spectrum (EI), m/z(rel intensity) 262 (M⁺. 1.6), 171 (4.4), 156 (3.2), 149 (9), 128 (3.3),114 (2.6), 109 (7), 105 (4.1), 99 (3.6), 92 (3.7), 91 (31), 81 (3.7), 77(5), 73 (100), 67 (4), 65 (6).

EXAMPLE 13 4-(1,3-Dioxolan-2-yl)-6-benzyloxyhexan-1-ol (15)

A 1 M solution of borane-methyl sulfide complex in dichloromethane (27mL, 27 mmol) was added dropwise to a stirred solution of the olefin 14(21 g, 80.36 mmol), prepared according to Example 12, in hexane (60 mL)at 0° C. The mixture was stirred for 3 h at room temperature, thencooled to 0° C., and then absolute ethanol (15 mL) was added dropwise,followed by 15% NaOH (15 mL) and 30% H₂O₂ (15 mL). The reaction mixturewas heated at reflux for 1 h. cooled to room temperature, and pouredinto water (200 mL). The organic layer was separated, and the aqueouslayer was extracted with ether (3×75 mL). The organic layers werecombined, dried over MgSO₄, and concentrated under reduced pressure. Thecrude product was chromatographed on a silica gel column, eluting with2% methanol in ether, to give the alcohol 15 (16.8 g, 74.6%) as aviscous liquid. IR (KBr)ν_(max) 3442, 3034, 2952, 2878, 1458, 1407,1364, 1206, 1103, 846, 742, 698 cm⁻¹; ¹HNMR (CDCl₃) δ 1.36-1.39 (m, 1H), 1.53-1.64 (m, 4 H), 1.79-1.90 (m, 3 H), 3.53-3.59 (m, 4 H),3.79-3.92 (m, 4 H), 4.49 (s, 2H), 4.78 (d, J=3.6 Hz, 1 H), 7.25-7.32 (m,5 H); ¹³CNMR (CDCl₃) δ 25.38, 29.23, 30.17, 38.19, 62.76, 64.78, 64.84,68.52, 72.72, 106.49, 127.39, 127.56, 128.23, 138.54: mass spectrum(EI), m/z (rel intensity) 280 (M⁺.0.02), 235(2.1), 220 (14), 219 (84),218 (69), 172 (15), 146 (23), 127 (15), 91 (35), 84 (9), 73 (10), 65(5.5).

EXAMPLE 14 4-(1,3-Dioxolan-2-yl)-6-benzyloxyhexanal (16)

The alcohol (15 (16.8 g, 59.92 mmol), prepared according to Example 13,was oxidized using 2 M (COCl)₂ (37.50 mL, 75 mmol), dry DMSO (10.6 mL,150 mmol), and triethylamine (43 mL, 300 mmol) as for the oxidation ofcompound 12. Similar work up as for 13 gave a crude product, which waspurified by column chromatography eluting with ether/hexane (2:1), togive the aldehyde 16 (4.8 g, 81%) as a colorless oil. IR (KBr)ν_(max)29.42, 2878, 2725, 1723, 1496, 1434, 1413, 1368, 1211, 1153, 1098, 1031,951, 742, 661 cm⁻¹; ¹HNMR (CDCl₃)δ 1.56-1.86 (m, 5 H), 2.52 (t, J=7.6Hz, 2H), 3.52-3.57 (m, 2H), 3.79-3.92 (m, 4 H), 4.48 (s, 2 H), 4.75 (d,J=3.3 Hz, 1 H), 7.25-7.34 (m, 5 H), 9.71 (s, 1 H); ¹³CNMR (CDCl₃)δ21.48, 29.33, 38.00, 41.71, 64.79, 68.73, 72.82, 106.28, 127.42, 127.55,128.55, 128.25, 138.48; mass spectrum (EI), m/z (rel intensity) 279(M⁺−1.7.5), 219(7), 171 (15), 144(8), 127(53), 91(31), 83(9), 73(100),65(4).

EXAMPLE 15 Methyl(3aSR,4RS)-3-benzyl-2,3,3a,4,5,7-hexahydro-4-[(2-ε-(1,3-dioxolan-2-yl)-4-methoxy)-1-butyl]-1H-pyrrolo[2,3-d]carbazole-6-carboxylates (18)

A solution of N^(b)-benzylindoloazapine 17 (3.8 g, 11.36 mmol), preparedaccording to the procedure described in Kuehne [12] and4-(1,3-dioxolan-2-yl)-6-methoxyhexanal (8, 2.75 g, 13.63 mmol), preparedaccording to Example 7, in dry toluene (75 mL) was heated at reflux for12 h using a Dean-Stark trap filled with 4 A molecular sieves, undernitrogen. The reaction mixture was cooled to room temperature andconcentrated on a rotary evaporator. The crude material was flashchromatographed on silica gel, eluting with ether/hexane (1:1), to givethe tetracyclic product 18 (4.86 g, 82%) as an inseparable mixture ofdiastereomers. TLC (SiO₂-ether/hexane 2:1) Rf0.32, CAS blue; UV (EtOH)λ_(max) 214, 226, 300, 330; IR (KBr) ν_(max) 3882, 2950, 2877, 1680,1610, 1478, 1465, 1438, 1281, 1247, 1206, 1118, 1050, 949, 748, 701cm⁻¹; mass spectrum (EI), m/z (rel intensity) 518 (M⁺.25), 385(21),332(17), 304(29), 341(12), 160(13), 91(88), 83(9), 73(100).

EXAMPLE 16 Enamine (21)

A solution of the mixture of tetracyclic diastereomers 18 (4.8 g, 9.04mmol), prepared according to Example 15, in glacial acetic acid (50 mL)was heated to 90° C. NaBH₄ (1.03 g, 17 mmol) was added in small portionsover a period of 10 min. The mixture was then poured over crushed ice,made basic with NH₄OH and extracted with ether (3×50 mL). The organicphase was dried over MgSO₄ and concentrated to give an inseparablemixture of cleavamine diasteromers 19 (4.4 g, 91%), which was useddirectly for hydrogenolysis. A solution of this crude cleaveamine 19(4.4 g), 10% Pd/C (1 g) in glacial acetic acid (100 mL) was subjected tohydrogenation at 1 atm of H₂ for 6 h. The reaction mixture was filteredthrough a plug of Celite and washed with acetic acid (2×20 mL) andmethanol (2×20 mL). The filtrate was basified with cold concentratedNH₄OH, and the resulting white precipitate was extracted with ether(4×25 mL). The organic layer was dried over MgSO₄ and concentrated togive the secondary amine acetal 20 (3.1 g, 87%), which, for hydrolysisof the acetal function, was dissolved in methanol (35 mL), glacialacetic acid (2 mL), and 10% HCl (35 mL). The mixture was stirred for 12h at room temperature under nitrogen, cooled to 0° C., and basified with15% NH₄OH in saturated brine. Extraction with ether (4×50 mL), dryingover MgSO₄, and concentration gave a crude product, which was flashchromatographed on silica gel, eluting with ether/hexane (1:1), to givethe enamine 21 (2.02 g, 76%).

EXAMPLE 17 18-Methoxycoronaridine (22)

The enamine 21 (2.0 g, 5.40 mmol), prepared according to Example 16, indry toluene (30 mL) was heated at 130° C. for 3 h. The reaction mixturewas cooled to room temperature and concentrated on a rotary evaporator.Flash chromatography of the crude product on silica gel, eluting withether/hexane, gave 18-methoxycoronaridine 22 (1.4 g, 70%) as a whitesolid, UV (EtOH)λ_(max) 228, 278, 285, 294 nm; ¹³CNMR δ 175.59, 136.50,134.80, 128.80, 121.92, 119.21, 118.41, 110.36, 110.00, 70.77, 58.00,57.60, 54.96, 53.09, 52.58, 51.58, 36.46, 33.90, 33.78, 31.95, 27.33,22.09.

EXAMPLE 18 Methyl(3aSR,4RS)-3-benzyl-2,3,3a,4,5,7-hexahydro-4-[(2-ε-(1,3-dioxolan-2-yl)-4-benzyloxy)-1-butyl]-1H-pyrrolo[2,3-d]carbazole-6-carboxylates(23a, 23b).

A solution of N^(b)-benzylindoloazepine 17 (5.0 g, 14.95 mmol), preparedaccording to Kuehne [12], and 4-(1,3-dioxolan-2-yl)-6-benzyloxyhexanal(16, 5.0 g, 17.94 mmol), prepared according to Example 14, in drytoluene (100 m L) was heated at reflux for 12 h, using a Dean-Stark trapfilled with 4A molecular sieves under nitrogen. The reaction mixture wascooled to room temperature and concentrated on a rotary evaporator. Theconcentrate was flash chromatographed on silica gel, eluting withether/hexane (1:1) to give 23a (4.4 g, 49%) and 23b (4.1 g, 46%).

EXAMPLE 19 Methyl3-benzyl-1,2,3,4,5,6,7,8-octahydro-5β-[(2-ε-(1,3-dioxolan-2-yl)-4-benzyloxy)-1-butyl]azonino[6,7]indole-7αand 7β carboxylates (24a,24b)

A solution of the tetracycle 23a (4.0 g, 6.73 mmol), prepared in Example18, in glacial acetic acid (40 mL) was heated at 90° C. NaBH₄ (0.77 g,20 mmol) was added in small portions over a period of 10 min. Themixture was then poured over crushed ice, made basic with NH₄OH, andextracted with ether (3×50 mL). The organic phase was dried over MgSO₄and concentrated. Flash chromatography of the crude materials on silicagel, eluting the ether/hexane (2:1), gave 24a (3.25 g, 81%) and 24b(0.65 g, 16%). Analogously, the tetracycle 23b was reduced to thecorresponding cleavamine esters 24c and 24d.

EXAMPLE 20 Enamine (26)

A solution of cleaveamines 24a and 24b (2.7 g, 4.51 mmol) and 10% Pd/C(1 g) in ethyl acetate (50 mL) and glacial acetic acid (5 mL) wassubjected to hydrogenolysis at 1 atm of H₂ for 16 hours. The reactionmixture was filtered through a plug of Celite and washed with aceticacid (2×20 mL) and methanol (2×20 m L). The filtrate was basified withcold concentrated NH₄OH, and the resulting white precipitate wasextracted with ether (4×25 mL). The organic layer was dried over MgSO₄and concentrated to give the secondary amine acetal 25 (1.75 g, 77%),which was dissolved in methanol (16 mL), glacial acetic acid (1 mL), and10% HCl (16 mL). The mixture was stirred in a round bottom flask coveredwith aluminum foil for 24 hours, at room temperature under nitrogen,then cooled to 0° C. and basified with 15% NH₄OH in saturated brine.Extraction with ether (4×50 mL), drying over MgSO₄, and concentrationgave a crude product, which was flash chromatographed on silica gel,eluting with ether/hexane (1:1), to give the enamine 26 (1.3 g, 86%).

EXAMPLE 21 18-Benzyloxycoronaridine (27)

The enamine 26 (2.0 g, 5.40 mmol), prepared in Example 20, in drytoluene (30 mL) was heated at 130° C. for 3 hours. The reaction mixturewas cooled to room temperature and concentracted on a rotary evaporator.Flash chromatography of the crude product on silica gel, eluting withether/hexane, gave the title product 27 (1.4 g, 70%) as a white solid.UV (EtOH) λ_(max) 214, 234, 278, 286, 294 nm; ¹³CNMR δ 175.44, 138.60,136.52, 135.47, 128.66, 128.15, 127.52, 127.45, 121.76, 119.07, 118.27,110.31, 110.13, 72.80, 68.38, 57.51, 54.86, 53.06, 52.56, 51.64, 36.33,34.12, 33.79, 31.87, 27.22, 21.94.

EXAMPLE 22 Albifloranine (28)

A mixture of 27 (1 g), prepared according to Example 21, 10% Pd/C (1 g),and ammonium formate (2 g) in dry methanol (50 mL) was heated at refluxfor 4 hours and then cooled to room temperature. The mixture wasfiltered through a Celite pad, and the filtrate was concentrated. Theresidue was flash chromatographed on silica gel, eluting with 1% MeOH inether, to give racemic albifloranine (28, 0.6 g, 75%), ¹³CNMR 175.17,135.87, 135.55, 128.37, 121.92, 119.17, 118.25, 110.39, 109.97, 59.27,57.93, 54.62, 52.90, 52.90, 52.68, 51.55, 36.32, 36.26, 34.62, 29.26,26.97, 21.48.

EXAMPLE 23 16-Hydroxymethyl-18-methoxyibogamine (29)

A solution of 2.0 g (5.4 mmol) of 18-methoxycoronaridine (22), preparedin accordance with Example 17, in 100 mL of dry tetrahydrofuran and 205mg (5.4 mmol) of LiAlH₄ was heated at reflux for 4 hours. Addition of 10g of sodium sulfate hexahydrate to the cooled mixture and stirring for 5hours, followed by filtration and concentration provided the carbinol 29(2.0 g, 99% yield), ¹³CNMR δ 135.45, 128.56, 121.15, 118.83, 117.98,111.05, 110.33, 71.05, 65.81, 58.57, 54.41, 53.32, 47.67, 36.54, 34,35,32.19, 30.61, 27.74, 21.83, 15.23.

EXAMPLE 24 Drugs

18-methoxycoronaridine was prepared by the method described in Example17, above. Ibogaine hydrochloride and harmaline hydrochloride werepurchased from the Sigma Chemical Company (St. Louis, Mo.). The R- andS-enantiomers of ibogamine and coronaridine (structures shown in [14])were prepared according to the methodology of Bornmann [7] and Kuehne[13]. Racemic desethylcoronaridine were synthesized using the proceduresdescribed in Bornmann [7]. Tabernanthine was supplied by P. Potier,CNRS, Institute of Chemistry of Natural Substances, Gif-sur-Yvette,France. All drugs were administered intrapertioneally; doses areexpressed as the hydrochloride salts. Different drugs and doses (orsaline) were administered to different groups of rats; rats wereinjected fifteen minutes before a morphine or cocaineself-administration session.

EXAMPLE 25 Subjects and Apparatus

The subjects were naive female Sprague-Dawley (Taconic, Germantown,N.Y.) rats approximately 3 months old and weighing 230-250 g at thebeginning of the experiment; female rats were used because they grow ata much slower rate than males and are less likely than males to outgrowtheir intravenous cannulas. Rats were housed singly in Wahmann hangingcages and maintained on a normal light/dark cycle (lights on/off at 7:00a.m./7:00 p.m.). All self-administration testing was conducted in twelveBRS/LVE operant test cages, each enclosed in a sound attenuated cubicle.Responses on either of two levers (mounted 15 cm apart on the front wallof each test cage) were recorded on an IBM compatible 386 computer witha Med Associates, Inc. interface. The intravenous self-administrationsystem consisted of polyethylene-silicone cannulas constructed accordingto the design of Weeks [15], BRS/LVE harnesses and commutators, andHarvard Apparatus infusion pumps (no. 55-222).

EXAMPLE 26 Self-Administration Procedures

Shaping of the bar-press response was initially accomplished by trainingrats to bar-press for water. Cannulas were then implanted in theexternal jugular vein according to procedures described by Weeks [15].Self-administration testing began with a single 24-h session followed bydaily 1-h sessions. 5 days (Monday-Friday) a week: rats were testedabout the same time each day, during the middle of the light cycle.Depending upon the group, a lever-press response produced either a 20 μl(morphine) or 50 μl (cocaine) infusion of drug solution (0.01 mg ofmorphine sulfate or 0.1 mg of cocaine hydrochloride) in about 0.2(morphine) or 0.5 (cocaine) seconds. Since all rats generally weighed250±20 g, each response delivered approximately 0.04 mg/kg of morphineor 0.4 mg/kg of cocaine; these doses are about two to four times thethreshold doses required for maintaining self-administration behavior[16.17]. One non-contingent drug infusion was administered at thebeginning of each session. Experiments to assess the effects of theiboga and harmala alkaloids were begun when baseline self-administrationrates stabilized (≦10% variation from one day to the next across 5days), usually after two weeks of testing.

EXAMPLE 27 Tremor Testing Procedures

Whole body tremors were assessed in two ways. Direct visual observationswere made of rats confined in a Plexiglas cylindrical (9 inches indiameter) enclosure; videotapes were sometimes made so that initialobservations could be confirmed at a later time. Tremors were rated asabsent, moderate or intense on a minute to minute basis for 30 min.beginning 15 min. after drug administration. An automated andquantitative technique, based on a method originally designed for miceby other investigators [18], was also developed and utilized. Briefly, aPLEXIGLAS™ enclosure was mounted on an audio speaker, the output ofwhich was connected to a Hewlett-Packard 3392A integrator: thesensitivity of the integrator was adjusted such that random locomotoractivity was generally ignored while large peaks representing tremorscould be readily identified. Tremors were recorded and counted for 30min. beginning 15 min. after drug administration.

EXAMPLE 28 Drug Self-Administration

FIGS. 1 and 2 shows the initial acute effects of 18-methoxycoronaridineand all of the remaining alkaloids, respectively, on morphine andcocaine self-administration. Each drug produced a dose-relateddepression of morphine and cocaine intake (ANOVA, P<0.001 in everycase). The potencies of the 18-methoxycoronaridine and the otheralkaloids were very similar and, as shown in FIG. 2, cannot bedistinguished, with the exception that desethylcoronaridine wasapproximately twice as potent as any of the other drugs. FIG. 3 showsthat ibogaine (40 mg/kg), R-ibogamine (40 mg/kg), R-coronaridine (40mg/kg), tabernanthine (40 mg/kg) and desethylcoronaridine (20 mg/kg),each administered for the first time, depressed morphine intake for atleast a day afterwards. FIG. 4 shows similar results for cocaine. Ineach of these cases, a group×days interaction was significant (P<0.05 ina two-way ANOVA), and paired t-tests with baseline values weresignificant (P<0.05-0.01) for days 1 and 2 in the indicated treatmentgroups. The extent of these aftereffects (one or more days later) ondrug self-administration varied substantially from rat to rat; responsesbeyond a day later (Day 2) ranged from no further effect to a prolongeddepression of morphine or cocaine intake, lasting up to several weeks ina few rats. In general, the aftereffects on cocaine intake were morevariable than those on morphine intake.

The effects of ibogaine and 18-methoxycoronaridine on motivated behaviorwere studied [1] by monitoring water bar pressing. Ibogaine (40 mg/kg)acutely depressed bar pressing for water for the first hour followingibogaine administration but bar pressing for water recovered to normalby the second day (FIG. 5). As shown in FIG. 6, this acute, short-termdecrease in motivated behavior was not observed following18-methoxycoronadine administration.

EXAMPLE 29 Tremorigenic Effects

Ibogamine (20-40 mg/kg), harmaline (10-40 mg/kg) and desethycoronaridine(10-40 mg/kg) were obviously tremorigenic for 3-4 h and no attempt wasmade to compare these drugs quantitatively. However, visual observationsand videotape recordings of 18-methoxycoronaridine (40 mg/kg) and bothR- and S-enantiomers of both ibogamine (40 mg/kg) and coronaridine (40mg/kg) indicated very little if any tremorigenic activity. The effectsof these latter drugs were therefore assessed using the automatedtesting procedure developed to quantitate tremors. Ibogains (40 mg/kg)and saline (1 ml/kg) were used as positive and negative controls,respectively. While ibogaine produced a significant increase inmovements indicative of tremors, the 18-methoxycoronaridine and theibogamine and coronaridine enantiomers had no effects that differedsignificantly from the effects of saline.

EXAMPLE 30 Neurotoxicity Studies

In a study similar to that conducted by O'Hearn and Molliver [5], femaleSprague Dawley (Charles River) rats were given IP injections of ibogaineand allowed to survive seven days after the last injection. Purkinjecell degeneration was evaluated with a Fink Heimer II stain; enhancedglial cell activity, with a GFAP antibody stain.

One set of animals received an ibogaine dose tested by O'Hearn andMolliver: 100 mg/kg per day for three consecutive days. All of theseanimals displayed bilaterally symmetric, parasagittal strips of Purkinjecell degeneration. The degeneration was more extensive than suggested byO'Hearn and Molliver, consistently occurring in the medial simple fobuleand Crus 1 as well as the vermis and intermediate regions of lobules 5,6, and 7. A second set of animals received a dose of18-methoxycoronaridine (100 mg/kg). No evidence of Purkinje celldegeneration was found in these animals.

Although the invention has been described in detail for the purpose ofillustration, it is understood that such detail is solely for thatpurpose, and variations can be made therein by those skilled in the artwithout departing from the spirit and scope of the invention which isdefined by the following claims.

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18. Remington, et al., A Simple Method for Quantifying Tremor inRodents, Pharmacol. Biochem. Behav., 4:721-723 (1976).

What is claimed is:
 1. A compound having the formula:

wherein n is from 0 to 8; R¹ is CH₂OH, CH(OH)R⁵, CH₂OR⁵, CO₂R⁵, C(O)NH₂,C(O)NHR⁵, C(O)NR⁵R⁶, C(O)NHNH₂, C(O)NHNHR⁵, C(O)NHNR⁵R⁶, C(O)NR⁵NH₂,C(O)NR⁵NHR⁶, C(O)NR⁵NR⁶R⁷, C(O)NHNH(C(O)R⁵), C(O)NHNR⁵(C(O)R⁶),C(O)NR⁵NH(C(O)R⁶), C(O)NR⁵NR⁶(C(O)R⁷), or C(O)R⁵; R² is H, unsubstitutedor substituted alkyl, YH, YR⁸, YC(O)R⁸, C(O)YR⁸, C(O)NH₂, C(O)NHR⁸,C(O)NR⁸R⁹, NH₂, NHR⁸, NR⁸R⁹, NHC(O)R⁸, NR⁸C(O)R⁹; R³ and R⁴ are the sameor different and are selected from the group consisting of H, halogens,unsubstituted or substituted alkyl, OH, OR¹⁰, NH₂, NHR¹⁰, NR¹⁰R¹¹,NHC(O)R¹⁰, or NR¹⁰C(O)R¹¹; R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ are the same ordifferent and are selected from the group consisting of unsubstitutedalkyl and substituted alkyl; R¹² is selected from the group consistingof H, unsubstituted alkyl, and substituted alkyl; and Y is O or S;provided that when n is 0, R² is substituted alkyl other than CH(OH)CH₃;further provided that when n is 2, R² is OH, R¹² is H, and both R³ andR⁴ are H, R¹ is not CO₂CH₃; and further provided that when n is 2, R² isH, R¹² is H, and R³ and R⁴ are the same or different and are selectedfrom the group consisting of H and OCH₃, R¹ is not CO₂CH₃; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, wherein R³ and R⁴ are H.
 3. A compound according to claim 1,wherein R¹² is H.
 4. A compound according to claim 1, wherein R¹ isCO₂R⁵.
 5. A compound according to claim 4, wherein R⁵ is CH₃.
 6. Acompound according to claim 1, wherein R¹ is CH₂OH.
 7. A compoundaccording to claim 1, wherein n is 2 and R² is YR⁸.
 8. A compoundaccording to claim 7, wherein Y is O.
 9. A compound according to claim8, wherein R⁸ is CH₃.
 10. A compound according to claim 8, wherein R⁸ isCH₂Ph.
 11. A compound according to claim 8, wherein R⁸ isCH₂OCH₂CH₂OCH₃.
 12. A compound according to claim 1, wherein n is 2 andR² is YH.
 13. A compound according to claim 12, wherein Y is O.
 14. Acompound according to claim 1, wherein n is 2 and R² is YC(O)R⁸.
 15. Acompound according to claim 14, wherein Y is O.
 16. A compound accordingto claim 15, wherein R⁸ is (CH₂)_(m)CH₃ and wherein m is from 0 to 20.17. A compound according to claim 16, wherein m is
 10. 18. A compoundaccording to claim 1, having the formula:


19. A compound according to claim 1, having the formula:


20. A compound according to claim 1, having the formula:


21. A compound according to claim 1, having the formula:


22. A compound according to claim 1, having the formula:


23. A composition comprising a compound according to claim 1 and apharmaceutically acceptable carrier.
 24. A method of treating asubject's addiction to an addictive substance, said method comprising:administering to a subject addicted to an addictive substance aneffective amount of a compound having the formula:

wherein n is from 0 to 8; R¹ is CH₂OH, CH(OH)R⁵, CH₂OR⁵, CO₂R⁵, C(O)NH₂,C(O)NHR⁵, C(O)NR⁵R⁶, C(O)NHNH₂, C(O)NHNHR⁵, C(O)NHNR⁵R⁶, C(O)NR⁵NH₂,C(O)NR⁵NHR⁶, C(O)NR⁵NR⁶R⁷, C(O)NHNH(C(O)R⁵), C(O)NHNR⁵(C(O)R⁶),C(O)NR⁵NH(C(O)R⁶), C(O)NR⁵NR⁶(C(O)R⁷), CN, or C(O)R⁵; R² is H,unsubstituted or substituted alkyl, YH, YR⁸, YC(O)R⁸, C(O)YR⁸, C(O)NH₂,C(O)NHR⁸, C(O)NR⁸R⁹, NH₂, NHR⁸, NR⁸R⁹, NHC(O)R⁸, or NR⁸C(O)R⁹; R³ and R⁴are the same or different and are selected from the group consisting ofH, halogens, unsubstituted or substituted alkyl, OH, OR¹⁰, NH₂, NHR¹⁰,NR¹⁰R¹¹, NHC(O)R¹⁰, or NR¹⁰C(O)R¹¹; R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ arethe same or different and are selected from the group consisting ofunsubstituted alkyl and substituted alkyl; R¹² is selected from thegroup consisting of H, unsubstituted alkyl, and substituted alkyl; and Yis O or S; provided that when n is 0, R² is selected from the groupconsisting of H, substituted alkyl, and unsubstituted alkyl; and furtherprovided that when n is 2, R² is H, R¹² is H, and both R³ and R⁴ are H,R¹ is not CO₂CH₃; or a pharmaceutically acceptable salt thereof.
 25. Amethod according to claim 4, wherein the addictive substance is selectedfrom the group consisting of opiates, stimulants, depressants,barbituates, and combinations thereof.
 26. A method according to claim5, wherein the addictive substance is an opiate.
 27. A method accordingto claim 6, wherein the opiate is heroin.
 28. A method according toclaim 5, wherein the addictive substance is a stimulant.
 29. A methodaccording to claim 8, wherein said stimulant is cocaine.
 30. A methodaccording to claim 4, wherein the addictive substance is ethanol.
 31. Amethod according to claim 4, wherein the addictive substance isnicotine.
 32. A method according to claim 24, wherein R³ and R⁴ are H.33. A method according to claim 24, wherein R¹² are H.
 34. A methodaccording to claim 24, wherein R¹ is CO₂R⁵.
 35. A method according toclaim 34, wherein R⁵ is CH₃.
 36. A method according to claim 24, whereinR¹ is CH₂OH.
 37. A method according to claim 24, wherein n is 2 and R²is YR⁸.
 38. A method according to claim 37, wherein Y is O.
 39. A methodaccording to claim 38, wherein R⁸ is CH₃.
 40. A method according toclaim 37, wherein R⁸ is CH₂Ph.
 41. A method according to claim 38,wherein R⁸ is CH₂OCH₂CH₂OCH₃.
 42. A method according to claim 24,wherein n is 2 and R² is YH.
 43. A method according to claim 42, whereinY is O.
 44. A method according to claim 24, wherein n is 2 and R² isYC(O)R⁸.
 45. A method according to claim 44, wherein Y is O.
 46. Amethod according to claim 45, wherein R⁸ is (CH₂)_(m)CH₃ and wherein mis from 0 to
 20. 47. A method according to claim 46, wherein m is 10.48. A method according to claim 24, wherein the compound has theformula:


49. A method according to claim 24, having the formula:


50. A method according to claim 24, wherein the compound has theformula:


51. A method according to claim 24, wherein the compound has theformula:


52. A method according to claim 24, wherein the compound has theformula:


53. A method according to claim 24, wherein the compound has theformula:


54. A method according to claim 24, wherein the compound is administeredin a dose of from about 1.0 to about 80 mg per kilogram of the subject'smass.